This grant proposes to explore the optimal treatment approach to depression in the patient with bipolar II disorder (BDII). BDII represents a critically understudied and important serious mental illness and is characterized by periods of major depression and periods of hypomania. There is now clear recognition of the stability of this diagnostic phenotype of bipolar disorder over time. Further research has revealed that the depressive symptoms in BDII occur frequently and the consequences of this can be severe, as the suicide risk is suggested to be higher than that in patients with BDI. The standard of care in treating depressed BDII patients is to use a mood stabilizer alone or a mood stabilizer and an antidepressant. However, there are virtually no controlled acute treatment trials specifically in patients with BDII to support the validity of these recommendations. Many patients with BDII dislike the idea of taking mood stabilizers and prefer instead to take only an antidepressant. Some open trials suggest good safety and tolerability of antidepressant monotherapy. Yet concerns exist that antidepressant monotherapy could destabilize mood in these patients. Whether taking an antidepressant as monotherapy actually exacerbates the illness (i.e., increases switches into mania or cycling, or intensifies hypomania) has never formally been tested. We propose a randomized, double-blind 16-week acute clinical trial comparing the efficacy and safety of sertraline monotherapy v. lithium monotherapy v. lithium plus sertraline combination in 207 patients with BDII in an acute depressive episode. The application is designed to assess acute treatment response, switch rates into hypomania/mania and side effects in patients with BDII depression undergoing treatment approaches. Primary aims are to compare the 3 treatment strategies in terms of effectiveness, adverse events (e.g., switch rates) and side effects (e.g., tolerability). We hypothesize that all treatment approaches will be equally efficacious in reducing depressive symptoms, but that there will be differences between treatments in regard to switch rates into hypomania/mania. We also hypothesize that the frequency of side effects will be significantly less in patients on SSRI monotherapy. Thus, secondary aims include assessment of patient satisfaction, which may affect compliance in the clinical setting.